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A triple antiviral therapy regimen of interferon beta1, lopinavir / ritonavir, and ribavirin shortened the mean time to viral negativity COVID-19 by 5 days in a small Hong Kong trial.
In an open, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to nasopharyngeal swab viral negativity was 7 days for 86 patients assigned to receive a 400 mg cycle of lopinavir and ritonavir for 14 days. 100 mg every 12 hours, ribavirin 400 mg every 12 hours and three doses of 8 million international units of interferon beta-1b every other day, compared to a median time to negativity of 12 days for patients treated with lopinavir / ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, of the Gleaneagles Hospital in Hong Kong, and his colleagues.
“Triple antiviral therapy with interferon beta-1b, lopinavir / ritonavir, and ribavirin was safe and superior to lopinavir / ritonavir alone to shorten virus clearance, alleviate symptoms, and facilitate discharge from patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.
Patients who received the combination also had a significantly shorter time to complete symptom relief as assessed by a national early warning score 2 (NEWS2, a system for detecting clinical decline in patients with acute illness) score of 0 (4 vs. 8 days, respectively); 3.92 risk ratio, P <.0001), and with a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).
The median hospital stay was 9 days for patients treated with the combination, compared to 14.5 days for controls (HR 2.72, P = .016).
In most patients treated with the combination, the SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat, and posterior oropharyngeal saliva and stool.
In addition, serum levels of interleukin 6 (IL-6), an inflammatory cytokine involved in cytokine storm that is frequently seen in patients with severe COVID-19 infections, were significantly lower on treatment days 2, 6 and 8 in combination-treated patients, compared to those treated with lopinavir / ritonavir alone.
“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs can rapidly suppress the amount of virus in a patient’s body, alleviate symptoms and reduce the risk to healthcare workers by reducing the duration and amount of viral clearance (when the virus is detectable and potentially transmissible). Also, the treatment combination seemed safe and well tolerated by patients, “said lead researcher Professor Kwok-Yung Yuen of the University of Hong Kong in a statement.
“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other medications is effective in patients with more serious illnesses (in whom the virus has had more time to replicate) “.
Plausible justification
Benjamin Medoff, MD, chief of the division of pulmonary medicine and critical care at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biological justification for the combination is plausible.
“I think this is a promising study suggesting that a regimen of interferon beta-1b, lopinavir / ritonavir, and ribavirin may shorten the duration of infection and improve symptoms in patients with COVID-19, especially if started early in the disease. , in less than 7 days of symptom onset, “he said in response to a request for expert analysis.
“The open nature and small size of the study limit the wide use of the regimen as noted by the authors, and it is important to emphasize that enrolled subjects did not have a very serious illness (not in the ICU). However, the study suggests that a larger, truly randomized study is warranted, “he said.
Reused AIDS drugs
Lopinavir / ritonavir is commonly used to treat HIV / AIDS worldwide, and researchers previously reported that antiviral agents combined with ribavirin reduced deaths and the need for intensive respiratory support among patients with SARS-CoV, the betacoronavirus that It causes an acute severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.
However, the SARS and MERS viral load peaks around days 7-10 after symptom onset, while the COVID-19 viral load peaks at the time of presentation, similar to influenza. Experience of treating hospitalized influenza patients suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation. ” the researchers wrote.
To test this, they enrolled adult patients admitted to one of Hong Kong’s six hospitals for virologically confirmed COVID-19 infections from February 10 to March 20, 2020.
A total of 86 patients were randomly assigned to the combination and 41 to lopinavir / ritonavir alone as controls, at the doses described above.
Patients who entered the trial less than 7 days after the onset of symptoms received the triple combination, with the interferon dose adjusted according to the day the treatment was started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those who started on days 5 or 6 received one dose of interferon. Patients recruited 7 days or more after symptom onset did not receive interferon beta-1b due to its proinflammatory effects.
In the post hoc analysis by day of treatment initiation, the clinical and virological results (except stool samples) were higher in patients admitted less than 7 days after the onset of symptoms for the 52 patients who received at least one dose of interferon plus lopinavir / ritonavir and ribavirin, compared to 24 patients randomized to the control arm (lopinavir / ritonavir only).
In contrast, among patients admitted and who started treatment on or after day 7 of symptoms, there was no difference between those who received lopinavir / ritonavir alone or in combination with ribavirin.
Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, which occurred in 52 of the 127 patients, fever in 48, nausea in 43, and elevated levels of alanine transaminase in 18. Side effects generally resolved within 3 days of initiation of treatment.
No serious adverse events were reported in the combination group. One patient in the control group had altered liver enzymes requiring discontinuation of treatment. No patient died during the study.
The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and the Sanming Project of Medicine. The authors and Dr. Medoff have no competing interests.
SOURCE: Hung IFN et al. Lancet. 2020 May 8. Doi: 10.1016 / S0140-6736 (20) 31101-6.
This article originally appeared on MDedge.com.
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